Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
J Med Chem. 2012 Dec 27;55(24):11022-30. doi: 10.1021/jm301476b. Epub 2012 Dec 14.
In an effort to address potential cardiotoxicity liabilities identified with earlier frontrunner compounds, a number of new 3,5-diaryl-2-aminopyridine derivatives were synthesized. Several compounds exhibited potent antiplasmodial activity against both the multidrug resistant (K1) and sensitive (NF54) strains in the low nanomolar range. Some compounds displayed a significant reduction in potency in the hERG channel inhibition assay compared to previously reported frontrunner analogues. Several of these new analogues demonstrated promising in vivo efficacy in the Plasmodium berghei mouse model and will be further evaluated as potential clinical candidates. The SAR for in vitro antiplasmodial and hERG activity was delineated.
为了解决早期先导化合物所识别出的潜在心脏毒性问题，合成了许多新型的 3,5-二芳基-2-氨基吡啶衍生物。一些化合物对多药耐药（K1）和敏感（NF54）株均表现出很强的抗疟活性，其活性达到纳摩尔级。与之前报道的先导类似物相比，一些化合物在 hERG 通道抑制试验中的活性显著降低。这些新类似物中的几种在伯氏疟原虫小鼠模型中表现出良好的体内疗效，将进一步作为潜在的临床候选药物进行评估。对体外抗疟和 hERG 活性的 SAR 进行了描述。
